MXPA01001097A - Prevention of migraine recurrence - Google Patents
Prevention of migraine recurrenceInfo
- Publication number
- MXPA01001097A MXPA01001097A MXPA/A/2001/001097A MXPA01001097A MXPA01001097A MX PA01001097 A MXPA01001097 A MX PA01001097A MX PA01001097 A MXPA01001097 A MX PA01001097A MX PA01001097 A MXPA01001097 A MX PA01001097A
- Authority
- MX
- Mexico
- Prior art keywords
- pharmaceutically acceptable
- eletriptan
- salt
- release
- composition
- Prior art date
Links
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- 239000000126 substance Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 230000001960 triggered Effects 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 235000019386 wax ester Nutrition 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
The invention relates to the use of eletriptan, or a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the prevention of migraine recurrence and to the use of a 5-HT1B/1D receptor agonist, or a pharmaceutically acceptable salt or composition thereof, for the manufacture of a dual-, sustained-, delayed-, controlled- or pulsed-release pharmaceutical composition for the prevention of migraine recurrence.
Description
RECURRENT MIGRAINE PREVENTION
DESCRIPTIVE MEMORY
This invention relates to the use of eletriptan for the manufacture of a medicament for the prevention of recurrent migraine. It has been described that 5-HT1 B / ID receptor agonists, such as compounds known as "pyrénones" are highly effective for the treatment of migraine Examples of such tpptan derivatives include eletriptan, sumatriptan, naratriptan, rizatriptan, zolmitriptan , almotpptan and frovatriptan The eletriptan, 3 - ([1-methyl? irrolidin-2 (R) -yl)] methyl) -5- (2-phenylsulphonylethyl) -1H-indole, is described in WO-A -96/06973 A preferred form of eletriptan hydrobromide salt is disclosed in WO-A-96 / 06842. WO-A-99/01135 discloses a pharmaceutical formulation comprising eletriptan hemisulfate and caffeine. two types: "migraine with aura" and "migraine without aura." Aura is the complex of focal neurological symptoms that initiates or accompanies an attack Migraine with aura is usually defined as an idiopathic recurrent disorder that manifests itself with attacks of neurological symptoms ine chemically detectable in the cerebral cortex or brainstem, which usually develop gradually for 5-20 minutes and last less than 60 minutes. Usually headache, nausea and / or photophobia follow the neurological symptoms of aura directly or after an interval without symptoms of less than one hour. Migraine headache usually lasts 4 to 72 hours but may be completely absent. 5 Migraine without aura is usually defined as an idiopathic recurrent headache that manifests itself in attacks that last from 4 to 72 hours. The typical characteristics of migraine headache are unilateral localization, pulsating quality, moderate or severe intensity, aggravation by routine physical activity and association with nausea, photophobia.
or phonophobia. Most patients have exclusively migraine attacks without aura. It also seems that patients who have frequent attacks with aura also have non-aura attacks. "Premonitory symptoms" may appear hours or a day or two before a migraine attack
(with or without aura). These symptoms often consist of general characteristics such as hyperactivity, hypoactivity, depression, craving for special foods, repetitive yawns, and similar atypical symptoms. Recurrent migraine is classified as a separate state from migraine itself and can be defined as the return of a headache from
moderate or severe migraine within 24 hours from the first dose of medication, from a migraine headache or mild state within 2 hours from the first dose of medication.
There is evidence that, although a triptan derivative can provide effective relief of a migraine headache, the use of said derivative actually results in the development of the recurrent migraine state at a rate that is characteristic of the particular triptan derivative. used. Currently, the typical incidence rate of recurrent migraine due to migraine attack is of the order of 30% when a triptan derivative is used. A clear distinction must be drawn between the treatment of migraine, which is to treat an established migraine headache, or the treatment of recurrent migraine, which is to treat an established recurrent migraine headache, and the prevention of recurrent migraine , which is to treat a patient in anticipation of a recurrent migraine headache to prevent that recurrence. It will be noted that not all patients suffer from recurrent migraine as defined above. To date, no 5-HTI B / ID receptor agonist has been shown to prevent recurrent migraine and this simply can not be predicted for any particular compound, although previously it was indicated for the treatment of migraine. Moreover, no "triptan" is currently indicated for the prevention of recurrent migraine. The reason that the prevention of recurrent migraine is unpredictable is that the etiology of recurrent migraine is not known. In addition, little is known about the characteristics of patients who have a tendency to experience
I '1 ^ ?? tÉÍÜ-ífl ?? "" - "^ ---------- ^^ A - * ..__-- * _ recurrent migraine or, alternatively, of the characteristics of migraine headaches that are likely to The publication "Cephalagia", 14, 330-338 (1994) describes that an oral dose of 100 mg of sumatriptan aborts approximately 60% of 5 migraine attacks in 2 hours, but that headaches can recur in 24 hours If a second sumatriptan tablet is given after 2 hours, it does not increase initial efficacy or prevent or delay recurrent migraine, however, administration of another dose of sumatriptan is highly effective in treating recurrent migraine 10 Furthermore, the publication "Neurology", 45, 1505-1509 (1995) describes that recurrent migraine may appear in 24 hours in approximately 40% of migraine attacks successfully treated with a subcutaneous dose of 6 mg of sumatriptan. However, an oral dose of 100 mg sumatr iptano taken 4 hours after the initial subcutaneous dose of 6 mg does not prevent recurrent migraine, but significantly delays the time of recurrent migraine. Surprisingly it has now been discovered that eletriptan can be used for the prevention of recurrent migraine. Accordingly, the present invention relates to the use of eletriptan, or a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the prevention of recurrent migraine.
^^^ «^^^^^^^ fo & ^? ^^^^^^^^^^ ^^^^^^^^^^^^^^^^^ g ^^ - ^^^^ ^^^^ J ^^^^^^^^^^^^^^^^^^^ - ^^^^^ - ^^^ S ^^^^^^^^ In addition, the present invention is refers to a method for the prevention of recurrent migraine comprising administering to a patient an effective amount of eletriptan, or a pharmaceutically acceptable salt or composition thereof. The pharmaceutically acceptable salts of the eletriptan include the acid addition salts and the base addition salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts, examples are the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, para-toluenesulfonate and pamoate. Suitable base addition salts are formed with bases which form non-toxic salts, examples being sodium, potassium, calcium, magnesium and zinc salts. For a review of suitable salts, see Berge et al., J. Pharm., Sci., 1977, 66, 1-19. Preferred eletriptan salts for use in the present invention are the hydrobromide and sulfate salts, including hemisulfate. Also included within the scope of the present invention are polymorphs, solvates and radiolabelled derivatives of eletriptan or a pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable solvates of eletriptan and its pharmaceutically acceptable salts include the hydrates thereof. A pharmaceutically acceptable salt of eletriptan can easily be prepared by mixing desired electrolyte and acid or base solutions, as appropriate. The salt can precipitate from the solution and be collected by filtration or can be recovered by evaporation of the solvent. The eletriptan, or a salt thereof, may be administered alone, but will generally be administered in a mixture with a suitable excipient, diluent or pharmaceutical carrier, selected with respect to the intended route of administration and standard pharmaceutical practice. For example, eletriptan, or a salt thereof, orally or sublingually may be administered in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate or controlled release applications. 15 Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, disintegrants such as starch, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinyl pyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, glyceryl benhenate and talc may be included. Solid compositions of a similar type can also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose or milk sugar, as well as high polyethylene glycols.
molecular weight. For the aqueous suspensions and / or elixirs, eletriptan, or a salt thereof, can be combined with various sweetening or flavoring agents, coloring material or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and 5 combinations of these. Eletriptan, or a salt thereof, may also be injected parenterally, for example intravenously, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or may be administered by infusion techniques. It is preferably used in the form of a sterile solution which may contain other substances, for example salts or glucose sufficient to make the solution dissolvable with the blood. Aqueous solutions should be suitably buffered (preferably at pH 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. For oral and parenteral administration to human patients the daily dose level of eletriptan, or salt thereof, will usually be from 0.1 to 4 mg / kg (in single or divided doses). Thus, the tablets or capsules of eletriptan, or a salt thereof, may contain from 5 to 240 mg, preferably from 5 to 100 mg, of active compound for single administration or of two or more at a time, according to be appropriate The doctor will determine the dose in any case
L - ^^ -. ^^., ^ - ^ -aia ^^ ..- ¿.? ---, «". ", _._-," ^ g fi ^^ tt-te- ^ -fc - ^^ - La -, --.--. - .. "_. .. _ > ____ »
real that will be more suitable for an individual patient and will vary with the age, weight and response of the particular patient. The above doses are examples of the average case. There may, of course, be individual cases where larger or smaller dosage ranges are required and these are within the scope of the invention. Eletriptan, or a salt thereof, can also be administered intranasally or by inhalation and is conveniently supplied in the form of a dry powder inhaler or spray aerosol presentation of a pressurized pack or a nebulizer with the use of a suitable impeller, example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1-tetrafluoroethane (HFA 134A [trademark] or 1, 1, 2,3,3,3-heptafluoropropane (HFA 227EA [trademark] , carbon dioxide or other suitable gas In case of a pressurized aerosol, the unit dose can be determined by providing a valve for discharging a measured quantity The pressurized container or nebulizer can contain a solution or suspension of the active component, for example using a mixture of ethanol and the impeller as a solvent, which may also contain a lubricant, for example sorbitan trioleate. or example of gelatin) for use in an inhaler or inhaler, may be formulated to contain a mixture of electrolyte powder, or a salt thereof, and a suitable powder base such as lactose or starch. Alternatively, eletriptan, or a salt thereof, can be administered intranasally by discharge from a
- «* ..-- -. -_ * & *. »non-pressurized unit or multi-dose pump-type device. Preferred formulations for intranasal administration include those comprising eletriptan, or a salt thereof, and caffeine or a cyclodextrin. Alternatively, eletriptan, or a salt thereof, can be administered in the form of a suppository or pessary, or it can be administered topically in the form of a solution, cream, ointment or powder for external use lotion. Eletriptan, or a salt thereof, can also be transdermally administered by the use of a dermal patch. For topical application to the skin, eletriptan, or a salt thereof, can be formulated, in the form of a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax as water. Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, paraffin, liquid, polysorbate 60, wax esters cetyl, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Preferred formulations of eletriptan, or a salt thereof, are described in WO-A-92/06973, WO-A-96/06842 and WO-A-99/01135. Particularly preferred formulations of eletriptan, or a salt thereof, for use in the prevention of recurrent migraine include
~ ^ ¡& ^ j ^^^? ^^ ^ '' «L ^^ _ ^ ^] ^^^^ i ^^ p and! -feg-« < --ga »-» -, ^ J-- * < . -, »< > - > & ---; »'Affu formulations of dual release, continuous release, controlled release, delayed release or pulsed release. The continuous release dosage forms are designed to release electrotriptan in the gastrointestinal tract of a patient for a continuous period of time following the administration of the dosage form to the patient. Suitable dosage forms include: (a) those in which the eletriptan, or a pharmaceutically acceptable salt thereof, is integrated in a matrix form that is released by diffusion or erosion, 10 (b) those in which the eletriptan, or a The pharmaceutically acceptable salt thereof is present in or on a multiparticle core which is coated with a velocity control membrane, (c) those in which the eletriptan, or a pharmaceutically acceptable salt thereof, is present in a dosage form containing
a coating impermeable to the medicament, in which the release is through a perforated aperture, (d) those in which the eletriptan, or a pharmaceutically acceptable salt thereof, is released through a semipermeable membrane, allowing the medicament to diffuse through the membrane or through
pores filled with liquid in the membrane, and (e) those in which the eletriptan is present in the form of an ion exchange complex that effectively functions as a "salt" form of controlled release of the active compound (e.g.
y¡ ^ y. ^ Jla-l-B- ..
the use of a suitable anion exchange resin, such as sodium polystyrenesulfonate). The skilled person will appreciate that some of the above means of achieving continuous release can be combined, for example, a matrix containing the active compound in a multiparticulate core and / or coated with an impermeable coating provided with an aperture can be formed. Pulse release formulations are designed to release the active compound by pulses for a continuous period of time following the administration of the dosage form to the patient. The release can be in the form of immediate or continuous release. Delayed release can be achieved by releasing the medication at particular points in the gastrointestinal tract or by releasing the medication after a certain time. The pulse release formulations may be in the form of tablets or multiparticles or a combination of both. Suitable dosage forms include: (a) release forms triggered by osmotic potentials (e.g. see U.S. Patent No. 3,952,741), (b) compressed-coated two-layer tablets (e.g. see U.S. Patent No. 5,464,633), (c) capsules containing an erodible plug (e.g. see U.S. Patent No. 5,474,784),
^ a, »-, -: - ,. ^, -. • -. ................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................ pH-dependent polymers, including shellac, phthalate derivatives, polyacrylic acid derivatives, and crotonic acid copolymers. The dual release formulations can combine the active compound in immediate release form with an additional active compound in continuous release form. For example, a bilayer tablet can be formed with one layer containing eletriptan in an immediate release form and the other layer containing eletriptan integrated in a matrix from which it is released by diffusion or erosion. The dual release formulations can also combine the active compound in immediate release form with another active compound in pulsed release form. For example, a capsule containing an erodible plug could release active compound initially, and after a predetermined period of time more active compound can be released in immediate or continuous release form. Preferred dual release drug profiles include: (a) immediate release followed by controlled release, (b) immediate release followed by zero order release, (c) immediate release followed by sigmoidal release, and (d) double pulse release .
Delayed release formulations are designed to release the active compound at a predetermined time after administration. The release of the delayed release formulations can be in the form of immediate release or continuous release. The controlled release formulations exert control with respect to the rate of release or the time of release, or both, of the active compound and include continuous, pulsed, dual and delayed release formulations. It has now surprisingly been discovered that the administration of a 5-HT1 B / ID receptor agonist, or a pharmaceutically acceptable salt thereof, in the form of a dual, continuous, delayed, controlled or pulsed release formulation, prevents the recurrent migraine. Other examples of 5-HTIB / .D receptor agonists that can be used include sumatriptan, naratriptan, rizatriptan, zolmitriptan, almotriptan and frovatriptan. The dual, continuous, delayed, controlled and pulsed release formulations that can be used are described above for eletriptan. Accordingly, the present invention further provides: (a) a dual, continuous, delayed, controlled and pulsed release pharmaceutical composition for the prevention of recurrent migraine, comprising a 5-HTI B / ID receptor agonist. Or a salt
^ da * ', --A.- A-J ^ aM «__ MfW __-- .. _. A | ! g & pharmaceutically acceptable gft thereof, and a pharmaceutically acceptable excipient, diluent or carrier, (b) the use of a 5-HT-? B receptor agonist. ID, or a pharmaceutically acceptable salt or composition thereof, for the manufacture of a dual release, continuous, delayed, controlled or pulsed pharmaceutical composition for the prevention of recurrent migraine, and (c) a method for the prevention of migraine Recurrent comprising the administration to a patient of an effective amount of a dual, continuous, delayed, controlled or pulsed release pharmaceutical composition comprising a 5-HT? B / -? receptor agonist. , or a pharmaceutically acceptable salt or composition thereof.
PHARMACOLOGICAL DATA
Patients suffering from an acute migraine attack 40 or 80 mg of eletriptan (in the form of a hydrobromide salt) were dosed in a tablet formulation. All patients who experienced migraine relief within 2 hours of the initial dose were given a second dose (same as initially given) of eletriptan (in the form of the hydrobromide salt) or placebo if recurrent migraine appeared. at 8 hours after the initial dosage or, if recurrent migraine did not appear, as close to 8 hours after the initial dosage as possible.
yg g ^^ * | M ^^^^ tój ^^^ fe ^ fe ^^^^^^^^^^^^^^^^^^^ Was the previous protocol repeated if the patient He experienced a second recurrent migraine attack at least 48 hours after the first attack. The results obtained for recurrent migraine (MR) rates, following the first and second migraine attacks, are tabulated below.
PICTURE
These tabulated data show that the eletriptan prevents the
recurrent migraine, since when a second dose of eletriptan was administered following the successful treatment of the initial headache, the number of patients who experienced a recurrent migraine headache was at least half compared to the placebo.
. > aí-it.ltt-. ¿, .. li¿a »j» »jiS- & - É - .. * jjt > -, -. «I. , - fl ^ _. jjj ^ j ^ f ^^ jjKM ^^^ j ^ jj ^^
Claims (29)
1. The use of eletriptan, or of a salt or pharmaceutically acceptable composition thereof, for the manufacture of a medicament for the prevention of recurrent migraine.
2. The use as claimed in claim 1, wherein the salt is a hydrobromide salt.
3. The use as claimed in claim 1, wherein the salt is a hemisulfate salt.
4. The use as claimed in claim 1, wherein the medicament comprises eletriptan hemisulfate and caffeine.
5. The use as claimed in claim 1, wherein the medicament comprises eletriptan or a pharmaceutically acceptable salt thereof.
6. The use as claimed in claim 1, wherein the medicament is a dual, continuous, controlled, delayed or pulsed release formulation of eletriptan or a pharmaceutically acceptable salt thereof.
7. The use as claimed in claim 6, wherein the medicament is a dual release formulation of eletriptan or a pharmaceutically acceptable salt thereof.
8. - A method for the prevention of recurrent migraine comprising the administration to a patient of an effective amount of eletriptan, or of a salt or pharmaceutically acceptable composition thereof.
9. A process as claimed in claim 8, wherein the salt is a hydrobromide salt.
10. A process as claimed in claim 8, wherein the salt is a hemisulfate salt.
11. A process as claimed in claim 8, wherein the composition comprises eletriptan hemisulfate and caffeine.
12. A procedure as claimed in the claim 8, wherein the composition comprises eletriptan or a pharmaceutically acceptable salt thereof and a cyclodextrin.
13. A method as claimed in claim 8, wherein the composition is a dual, continuous, controlled, delayed or pulsed release formulation of eletriptan or a pharmaceutically acceptable salt thereof.
14. A process as claimed in claim 13, wherein the composition is a dual release formulation of eletriptan or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition for the prevention of recurrent migraine comprising eletriptan, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or vehicle thereof. -É "'- * - * ™« - *? ** ¿- - .. ".-, - - .....-._.« ______... = - to ______ ^. a ^^. ..y ^ * «
16. - A dual-release, continuous, controlled, delayed or pulsed pharmaceutical composition for the prevention of recurrent migraine, comprising eletriptan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or carrier thereof.
17. A composition as claimed in the claim 16, which is a dual release composition.
18. A composition as claimed in claims 15, 16 or 17 further comprising caffeine or a cyclodextrin.
19. A dual-release, continuous, delayed, controlled or pulsed pharmaceutical composition for the prevention of recurrent migraine, comprising a 5-HT-IB / -ID receptor agonist, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or vehicle thereof.
20. A dual release pharmaceutical composition as claimed in claim 19.
21. A pharmaceutical continuous release composition as claimed in claim 19.
22. A delayed release pharmaceutical composition as claimed in claim 19.
23.- A controlled release pharmaceutical composition as claimed in claim 19. _ ^ * M «* - - - ~ ~ - '-» - - ^ - - - - - - - - - - - - - - - - - - - ~
24. - A pharmaceutical composition for pulse release as claimed in claim 19.
25.- A composition as claimed in any of claims 19 to 24, in which the HTI receptor agonist B / -ID is selected from the group consisting of sumatriptan, naratriptan, rizatriptan, zolmitriptan, almotriptan and frovatriptan.
26. The use of a 5-HT-I B / ID receptor agonist, or a salt or pharmaceutically acceptable composition thereof, for the manufacture of a dual, continuous, delayed, controlled or pulsed release composition for the recurrent migraine prevention.
27. The use as claimed in claim 26, wherein the 5-HT B D receptor agonist is selected from the group consisting of sumatriptan, naratriptan, rizatriptan, zolmitriptan, almotriptan and frovatriptan.
28. A method for the prevention of recurrent migraine comprising the administration to a patient of an effective amount of a dual release, continuous, delayed, controlled or pulsed pharmaceutical composition, comprising a 5-HTα receptor agonist. B 1 D, or a pharmaceutically acceptable salt thereof.
29. A procedure as claimed in the claim 28, wherein the 5-HT-? B? D receptor agonist is selected from the group consisting of sumatriptan, naratriptan, rizatriptan, zolmitriptan, almotriptan and frovatriptan. ^^^^^^ g ^^ g ^^^^^^^ _ ^ - ^^^^^^ --- ^^^^^^^ gg ^ íggg ^^^^^^^^ g ^^ ^^^
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB9816556.6 | 1998-07-30 |
Publications (1)
Publication Number | Publication Date |
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MXPA01001097A true MXPA01001097A (en) | 2001-11-21 |
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